PROJECT SUMMARY/ABSTRACT HIV treatment and prevention approaches are evolving in response to advancements in pharmacotherapies. Yet in the United States substance using members of key populations such as men of color who have sex with men (MoCSM) face socio-behavioral barriers that inhibit access and adherence across the HIV Care and Prevention Cascades that produce HIV relevant biological changes. Elucidation of how substance use affects basic, biological, behavioral, and social aspects of HIV is vital to advance HIV prevention and treatment. In response to NIDA RFA-DA-18-011 Cohort Studies of HIV/AIDS and Substance Use (U01), the University of California, Los Angeles (UCLA) seeks to continue the MSM and Substances Cohort at UCLA Linking Infections Noting Effects (MASCULINE or the ?mSTUDY?) established in 2013 and to extend the scientific opportunities it offers for another five years. Our proposed competitive renewal will sustain and dynamically refresh the cohort of substance-using HIV-seropositive (HIV+) and high-risk HIV-seronegative (HIV-) MoCSM by retiring older, non-substance-using members and adding younger substance-users. If renewed, this cohort will continue to add specimens to our well-characterized, extensive biobehavioral repository and to provide a platform for high-impact science. Substance use continues to effect adherence to treatment and prevention regimens thereby sustaining high prevalence networks. Proposed investigators lead the science on studying associations between drug use, behaviors, and infectious disease and will contribute a broad portfolio of interdisciplinary work from immunology and basic science to epidemiology, prevention and treatment. This cohort of MoCSM will characterize: (i) effects of substance use on acquisition of HIV and other sexually transmitted infections (STIs: gonorrhea, Chlamydia, syphilis); (ii) the extent to which substance use in MoCSM facilitates behaviors that transmit HIV compared to non-drug using MoCSM (iii) the effects of substance use and HIV on the mucosal environment; (iv) effect of substance use on HIV disease progression; and interactions between substance use and HIV infection on the inflammatory response. We identify the direct ways stimulants, cannabis and other substance use in combination with specific behaviors can change HIV transmission and progression dynamics in multiple compartments via immune function and the microbiome. The application also proposes to expand an already robust biorepository with specimens available for the broader research community. This cohort will be comprised of 514 MoCSM with repeated data visits. At least half will be active substance users and younger than age 30. With a fully enrolled cohort, the mSTUDY has begun to produce high impact publications and spinoff research projects with newly integrated datasets of large sample sizes. The next cycle will further stimulate basic and biologically innovative science from collaborating investigators, newly established collaborations with other NIDA cohorts, and externally funded scientists and generate high impact future science.